Flavone acetic acid (FAA) causes rapid necrosis of a variety of solid human tumors in rodents, which appears to involve vascular collapse and a complex network of cytokines produced by cells of the immune system. In vivo studies indicate that FAA selectively affects tumor endothelium. Normal endothelium does not appear to be adversely affected. We report that FAA inhibited the proliferation of normal monkey aortic endothelial cells (MAEC) in the absence of gross cell damage or impairment of acetylated low density lipoprotein (LDL) uptake. FAA prevented the formation of tubelike structures when MAEC were cultured on a layer of Matrigel. Both nitric oxide and tumor necrosis factor (TNF) have been implicated in FAA induced tumor necrosis in vivo. The cytostatic effect of FAA on MAEC was not abolished by preventing the synthesis of nitric oxide. TNF partially reduced the rate of cell growth, with treated cells reaching confluence 2-3 days later than untreated MAEC. Preincubation of MAEC with anti-TNF antibody prevented TNF, but not FAA mediated perturbations of cell growth. Similar inhibitory effects on replication of human umbilical vein endothelial cells were observed with FAA. We then investigated the effect of FAA on the signal transduction pathways commonly used by growth factors. FAA did not alter protein kinase C (PKC) activity. However, we have noted marked similarity between the effects of FAA and the tyrosine kinase inhibitor herbimycin A on MAEC proliferation. A syngeneic rat tumor model was established which is well suited for studies of the effect of FAA on tumor growth and metastatic dissemination. Preliminary findings revealed a drastic decrease in subcutaneous tumor size within five days following a single intraperitoneal injection of FAA. This model will be used to characterize the effects of FAA on tumor vasculature, as well as on immunological and tumor derived factors.